Actinic keratosis is defined as a malignant neoplasm of epidermal keratinocytes triggered by exposure to ultraviolet radiation and is an early stage in the continuous process from atypical keratinocyte proliferation to the development of non-melanoma skin cancer (NMSC).
It has been long known that the development of actinic keratosis is associated and frequently preceded by subclinical disorders in the epidermis surrounding or to surround the actinic keratosis lesion. These subclinical disorders make up the so-called subclinical field cancerization. A high probability for developing actinic keratosis lesions and/or squamous cell cancer has been observed in field cancerization (Boudewjin, J. M. et al. 2003. A Genetic Explanation of Slaughter's Concept of Field Cancerization: Evidence and Clinical Implications. Cancer Research 63:1727-1730). Skin field cancerization is the skin area that shares a genetic risk for developing skin carcinoma due to the damage caused by ultraviolet radiation. It includes areas where the actinic keratosis lesion or non-melanoma skin cancer are already present and show cell damage (e.g. cell atypia) or histological damage (e.g. parakeratosis), but also morphologically normal areas that show at the molecular level the same genetic changes induced by ultraviolet light that characterize squamous cell carcinoma of the skin, e.g. mutations or changes in TP53 gene expression (Padilla, R. S. et al. 2010. Gene Expression Patterns of Normal Human Skin Actinic Keratosis, and Squamous Cell Carcinoma. Arch. Dermatol. 146(3):288-293). In this invention we define subclinical field cancerization as the skin area with genetic changes at molecular level (alteration of expression level of proteins such as TP53, p21 or PCNA and decreased expression levels of genes such as PPP1R14A (CPI-17)) induced by ultraviolet light and that does not show clinical evidence of actinic keratosis lesion or non-melanoma skin cancer.
Therefore, there has been an interest in finding therapies that may reduce subclinical field cancerization and, optionally, also existing actinic keratosis lesions and/or non-melanoma skin cancer (NMSC). One of the most common treatments is the topical application of 5% Imiquimod cream. The application of this cream causes an inflammatory response in the field cancerization, while it does not cause this reaction in normal cells, indicating a specific reaction in impaired cells.
On the other hand, the use of photolyase enzymes has been described to repair the DNA damage caused by ultraviolet radiation, more specifically to remove pyrimidine base dimers (CPDs) that are produced when skin is exposed to ultraviolet radiation (Stege, H.2001. Effect of xenogenic repair enzymes on photoimmunology and photocarcinogenesis. Journal of Photochemistry 65:105-108). According to this article, the topical application of photolyase, in addition to removing pyrimidine base dimers, allowed for reducing the immunodepression induced by UVB radiation.
Sun protection creams are also found in the market (ERYFOTONA® AK-NMSC by ISDN, S.A.) that contain photolyase in liposomes, recommended for preventing the occurrence of actinic keratosis and non-melanoma skin cancer.
However, there was no evidence to date that the topical application of photolyase allows for reducing or improving the subclinical skin field cancerization associated with actinic keratosis and/or non-melanoma skin cancer (NMSC).